The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in part by regulating insulin secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes has recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in glucose metabolism and diabetes, the pancreatic beta cell is considered a primary target for neuromodulation. To propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet nerves impact insulin secretion from the beta cell. The objective of this application is to determine the mechanisms nerves use to control insulin secretion. Recent anatomical studies show that sympathetic and sensory nerves innervate the human islet, but parasympathetic innervation is sparse. Importantly, these nerves do not contact beta cells directly but densely innervate the islet vasculature. We therefore hypothesize that autonomic nerves control blood flow and vascular permeability to adjust insulin release into the bloodstream. The rationale for the proposed research is that these mechanisms of nerve action could be intervention targets for neuromodulation in human beings, which is relevant to the mission of the NIH. Guided by preliminary data, our hypothesis will be tested by pursuing two specific aims: (1) determine the functional role of sympathetic innervation for insulin secretion, and (2) determine the functional role of sensory nerves for insulin secretion. Under the first aim, we will test that sympathetic nerves target vascular pericytes to change blood flow. We will transplant human and mouse islets into the eye of diabetic mice. In the eye, islet grafts restore normoglycemia and can be monitored non-invasively. Importantly, islet grafts are revascularized and reinnervated in patterns that resemble those of islets in the pancreas. We will stimulate, inhibit, and ablate sympathetic input to islet grafts and determine the effects on islet blood flow and simultaneously measure the effects on insulin plasma levels and glycemia. We will also test whether chronic activation of sympathetic nerves prevents the derangement of islet vasculature in mouse models of type 2 diabetes. Under the second aim, we will test that sensory nerves respond to local perturbations in the islet microenvironment to change the vascular permeability. To determine what activates sensory nerves in the islet, we will use mice that express functional indicators in sensory neurons and measure activity in nerve terminals in the islet in living pancreas slices and in vivo in neuronal cell bodies of the nodose ganglion after stimulating or injuring the islet. We will also activate sensory nerve chronically to test the impact on islet health in mouse models of type 2 diabetes. The proposed research is significant because the research plan takes into account the innervation pattern of the human islet and uses those aspects of mouse islet innervation that are representative of the human situation. Knowing how nerves control insulin secretion is crucial to propose neuromodulation as a therapeutic approach in diabetes.